ebook_ADHD2019

18 Rohde, Buitelaar, Gerlach & Faraone altered in blood and urine of drug-naïve/drug-free patients with ADHD compared to healthy individuals. 1 Some of the metabolites were also associated with symp- tom severity of ADHD and/or the response to ADHD medication. The serendipitous finding that methylphenidate (MPH) treats ADHD symp- toms started research into the role of dopaminergic neurotransmission in the pathophysiology of ADHD. This research was soon extended to include nore- pinephric neurotransmission pathways, since the re-uptake inhibitory action of MPH and other psychostimulants is not selective to the dopamine transporter receptor, but also affects the norepinephrine transporter function. Later, also se- rotonergic neurotransmission was found to be involved. Thereafter, we review the involvement of other neurotransmission systems in ADHD. DOPAMINE The neurotransmitter dopamine is involved in regulation of motor activity and limbic functions, but also plays a role in attention and cognition, especially exe- cutive functioning 2 and reward processing. 3 It is a key-contributor to behavioural adaptation and to anticipatory processes necessary for preparing voluntary action following intention. 4 In addition to the fact that the function of dopamine fits well with the signs and symptoms observed in people with the disorder, dopamine cir- cuit dysfunction has been implicated in ADHD based on different experimental evidence. 5 Dopamine-producing cells are localized in the midbrain substantia ni- gra pars compacta and the ventral tegmental area. From there, three projection pathways can be distinguished: the nigrostriatal pathway, which originates from the substantia nigra and projects to the dorsal striatum (caudate nucleus and puta- men); the mesolimbic pathway, which projects from ventral tegmentum to limbic system structures, in particular the ventral striatum (nucleus accumbens), hippo- campus, and amygdala; the mesocortical pathway also originating in the ventral tegmental area, which projects to the cerebral cortex, the medial prefrontal areas in particular. 6 As indicated above, the dopamine transporter – which is the most important molecule in the regulation of dopamine signalling in most areas of the brain – is the main target of stimulants like MPH and also dexamphetamine, the most fre- quently used prescription drugs for the treatment of ADHD symptoms. These drugs block the dopamine transporter and lead to an increase in dopamine con- centration, particularly in the parts of the basal ganglia that are highest in the ex- pression of the transporter, the striatum. 7 This effect is due to the blockade of the transporter molecule in the case of MPH, and due to both transporter blockade and stimulation of dopamine release/block of breakdown through monoamine oxi- dase in the case of dexamphetamine. 8 The dopamine transporter protein (DAT) and its gene ( DAT1 , official name SLC6A3 ) have thus received most attention in